Feasibility of pharmacy-based research opportunity to enhance community testing and surveillance.

Background: Approximately 89% of the US population lives within five miles of a community pharmacy, which provides a network of geographically distributed recruitment nodes for testing and surveillance of infection and disease.

Objectives: Establish feasibility of Pharmacy-based Research Opportunities To Enhance Community Testing and Surveillance in the context of SARS-CoV-2 infection in a community pharmacy setting with University of Kentucky serving as the coordinating center and research hub for sample analysis.

Methods: Two community pharmacies in Kentucky served as community-based recruitment sites to assess SARS-CoV-2 exposure through longitudinal (5 visits over 56 days) collection of nasal swabs and blood samples from subjects.

Does serous tubal intraepithelial carcinoma (STIC) metastasize? The clonal relationship between STIC and subsequent high-grade serous carcinoma in BRCA1/2 mutation carriers several years after risk-reducing salpingo-oophorectomy.

Objective: The majority of high-grade serous carcinomas (HGSC) of the ovary, fallopian tube, and peritoneum arise from the precursor lesion called serous tubal intraepithelial carcinoma (STIC). It has been postulated that cells from STICs exfoliate into the peritoneal cavity and give rise to peritoneal HGSC several years later. While co-existent STICs and HGSCs have been reported to share similarities in their mutational profiles, clonal relationship between temporally distant STICs and HGSCs have been infrequently studied and the natural history of STICs remains poorly understood.

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRAS-Mutated NSCLC Treated With Sotorasib.

Introduction: For patients with KRAS-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression.

Methods: Patients with KRAS-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372).

Using team-based precision medicine to advance understanding of rare genetic brain disorders.

We describe a multidisciplinary teamwork approach known as "Operation IDD Gene Team" developed by the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) at the Albert Einstein College of Medicine. This initiative brings families affected by rare genetic diseases that cause intellectual and developmental disability together with physicians, basic scientists, and their trainees.

Mutation Analysis of Pancreatic Juice and Plasma for the Detection of Pancreatic Cancer.

Molecular profiling may enable earlier detection of pancreatic cancer (PC) in high-risk individuals undergoing surveillance and allow for personalization of treatment. We hypothesized that the detection rate of DNA mutations is higher in pancreatic juice (PJ) than in plasma due to its closer contact with the pancreatic ductal system, from which pancreatic cancer cells originate, and higher overall cell-free DNA (cfDNA) concentrations. In this study, we included patients with pathology-proven PC or intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia (HGD) from two prospective clinical trials (KRASPanc and PACYFIC) for whom both PJ and plasma were available.

Machine learning-based somatic variant calling in cell-free DNA of metastatic breast cancer patients using large NGS panels.

Next generation sequencing of cell-free DNA (cfDNA) is a promising method for treatment monitoring and therapy selection in metastatic breast cancer (MBC). However, distinguishing tumor-specific variants from sequencing artefacts and germline variation with low false discovery rate is challenging when using large targeted sequencing panels covering many tumor suppressor genes. To address this, we built a machine learning model to remove false positive variant calls and augmented it with additional filters to ensure selection of tumor-derived variants.

Chromosomal mosaicism in human blastocysts: a cytogenetic comparison of trophectoderm and inner cell mass after next-generation sequencing.

Research Question: What is the incidence of chromosomal mosaicism in human blastocysts and can a single trophectoderm (TE) biopsy accurately predict the chromosomal constitution of the inner cell mass (ICM)?

Design: Observational study in 46 surplus cryopreserved preimplantation embryos of unknown chromosomal constitution. For each embryo, a TE biopsy was performed and the ICM was collected separately. Both samples underwent next-generation sequencing (NGS) for cytogenetic analysis and were classified as chromosomally normal, abnormal or mosaic.

Sexual Dysfunction in Women With Multiple Sclerosis: Expectations Regarding Treatment and Information, and Utility of the SEA-MS-F Questionnaire.

Introduction: Sexual dysfunction is a common complaint in female with multiple sclerosis (MS), however this problem is not often considered in the medical and psychological care.

Aim: To evaluate expectations regarding treatment and information for sexual dysfunction in women with multiple sclerosis using the SEA-MS-F (Sexual Dysfunction Management and Expectations Assessment in Multiple sclerosis - Female) questionnaire, and to gain an understanding of the relationship between their expectations, demographic factors and medical factors known to promote sexual dysfunction.

Methods: A prospective epidemiological, descriptive, analytical, multicentre study was carried out over 15 months on adult women suffering from MS.

Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma Demonstrates High Intertumor and Intratumor Heterogeneity.

Introduction: Intertumor and intratumor heterogeneity may explain the diagnostic challenge and limited efficacy of chemotherapy for primary sclerosing cholangitis-associated cholangiocarcinoma (PSC-CCA). In this study, tumor heterogeneity was assessed through p53 and p16 protein expression analysis and next-generation sequencing (NGS) of TP53 and CDKN2A genetic alterations in PSC-associated CCA.

Methods: Formalin-fixed paraffin-embedded tissue samples from resection material of patients with PSC-CCA or patients with PSC diagnosed with biliary dysplasia were selected.

Transcriptomic Properties of HER2+ Ductal Carcinoma In Situ of the Breast Associate with Absence of Immune Cells.

The identification of transcriptomic alterations of HER2+ ductal carcinoma in situ (DCIS) that are associated with the density of tumor-infiltrating lymphocytes (TILs) could contribute to optimizing choices regarding the potential benefit of immune therapy. We compared the gene expression profile of TIL-poor HER2+ DCIS to that of TIL-rich HER2+ DCIS. Tumor cells from 11 TIL-rich and 12 TIL-poor DCIS cases were micro-dissected for RNA isolation.

Does positive MGMT methylation outbalance the limitation of subtotal resection in glioblastoma IDH-wildtype patients?

Background: The impact on survival of complete resection (CR) in patients with malignant glioma and MGMT promoter methylation on adjuvant therapy strategies has been proven in the past. However, it is not known whether a MGMT promoter methylation can compensate a subtotal resection. Therefore, we analyzed the progress of postoperative residual tumor tissue depending on the molecular tumor status.

Caregiver-reported characteristics of children diagnosed with pathogenic variants in KDM5C.

Loss of function variants in the lysine demethylase 5C (KDM5C) gene account for approximately 0.7-2.8% of X-linked intellectual disability (ID) cases and pose significant burdens for patients and their caregivers.

Validation of a Targeted Next-Generation Sequencing Panel for Tumor Mutation Burden Analysis: Results from the Onconetwork Immuno-Oncology Consortium.

Tumor mutation burden (TMB) is evaluated as a biomarker of response to immunotherapy. We present the efforts of the Onconetwork Immuno-Oncology Consortium to validate a commercial targeted sequencing test for TMB calculation. A three-phase study was designed to validate the Oncomine Tumor Mutational Load (OTML) assay at nine European laboratories.

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN).

Histological diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN), the precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC), can be challenging, as features of dVIN may mimic those of non-dysplastic dermatoses. To aid the diagnosis, p53-immunohistochemistry (IHC) is commonly used, and mutant expression patterns are used to support a histological diagnosis of dVIN. However, a proportion of dVIN can show wild-type p53-expression, which is characteristic of non-dysplastic dermatoses.

A Third Luminous Shark Family: Confirmation of Luminescence Ability for Zameus squamulosus (Squaliformes; Somniosidae).

Since recently, shark's bioluminescence has been recorded from two Squaliformes families, the Etmopteridae and Dalatiidae. Pictures of luminescence, light organ morphologies and physiology of the luminous control have been described for species of the Etmopteridae and Dalatiidae families. In 2015, a third luminous family, Somniosidae, was assumed to present a bioluminescent species, Zameus squamulosus.

Residual force enhancement due to active muscle lengthening allows similar reductions in neuromuscular activation during position- and force-control tasks.

Background: Residual torque enhancement (rTE) is the increase in torque observed during the isometric steady state following active muscle lengthening when compared with a fixed-end isometric contraction at the same muscle length and level of neuromuscular activation. In the rTE state, owing to an elevated contribution of passive force to total force production, less active force is required, and there is a subsequent reduction in activation. In vivo studies of rTE reporting an activation reduction are often performed using a dynamometer, where participants contract against a rigid restraint, resisting a torque motor.

Fast detection of FOXF1 variants in patients with alveolar capillary dysplasia with misalignment of pulmonary veins using targeted sequencing.

Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal congenital lung disorder associated with heterozygous variants in the FOXF1 gene or its regulatory region. Patients with ACD/MPV unnecessarily undergo invasive and expensive treatments while awaiting a diagnosis. The aim of this study was to reduce the time to diagnose ACD/MPV by developing a targeted next-generation sequencing (NGS) panel that detects FOXF1 variants.

Mutations in Serum Circulating Cell-Free Tumor DNA As Longitudinal Biomarker for High-Grade Serous Ovarian Cancer.

The aim of this study was to determine an optimal workflow to detect mutations in baseline and longitudinal serum cell free DNA (cfDNA) from high-grade serous ovarian carcinomas (HGSOC) patients and to define whether mutations are suitable as biomarker for disease. was investigated in tissue and archived serum from 20 HGSOC patients by a next-generation sequencing (NGS) workflow alone or combined with digital PCR (dPCR). AmpliSeq™-focused NGS panels and customized dPCR assays were used for tissue DNA and longitudinal cfDNAs, and Oncomine NGS panel with molecular barcoding was used for baseline cfDNAs.

Explaining sudden infant death with cardiac arrhythmias: Complete exon sequencing of nine cardiac arrhythmia genes in Dutch SIDS cases highlights new and known DNA variants.

Previous studies suggested that Sudden Infant Death Syndrome (SIDS) can partially be genetically explained by cardiac arrhythmias; however, the number of individuals and populations investigated remain limited. We report the first SIDS study on cardiac arrhythmias genes from the Netherlands, a country with the lowest SIDS incidence likely due to parent education on awareness of environmental risk factors. By using targeted massively parallel sequencing (MPS) in 142 Dutch SIDS cases, we performed a complete exon screening of all 173 exons from 9 cardiac arrhythmias genes SCN5A, KCNQ1, KCNH2, KCNE1, KCNE2, CACNA1C, CAV3, ANK2 and KCNJ2 (∼34,000 base pairs), that were selected to harbour previously established SIDS-associated DNA variants.

Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification.

Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5-41% of breast cancers.

Tumor mutational load, CD8 T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients.

Objectives: A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8 T cell infiltration, HLA class-I and PD-L1 expression in the tumor.